Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk
Authors: Jefferson L. Triozzi, Ryan S. Hsi, Guanchao Wang, Elvis A. Akwo, Lee Wheless, Hua-Chang Chen, Ran Tao, T. Alp Ikizler, Cassianne Robinson-Cohen, Adriana M. Hung, Sumitra Muralidhar, Jennifer Moser, Jennifer E. Deen, Philip S. Tsao, J. Michael Gaziano, Elizabeth Hauser, Amy Kilbourne, Shiuh-Wen Luoh, Michael Matheny, Dave Oslin, Lori Churby, Stacey B. Whitbourne, Jessica V. Brewer, Shahpoor (Alex) Shayan, Luis E. Selva, Saiju Pyarajan, Kelly Cho, Scott L. DuVall, Mary T. Brophy, Brady Stephens, Todd Connor, Dean P. Argyres, Tim Assimes, Adriana Hung, Henry Kranzler, Samuel Aguayo, Sunil Ahuja, Kathrina Alexander, Xiao M. Androulakis, Prakash Balasubramanian, Zuhair Ballas, Jean Beckham, Sujata Bhushan, Edward Boyko, David Cohen, Louis Dellitalia, L. Christine Faulk, Joseph Fayad, Daryl Fujii, Saib Gappy, Frank Gesek, Jennifer Greco, Michael Godschalk, Todd W. Gress, Samir Gupta, Salvador Gutierrez, John Harley, Kimberly Hammer, Mark Hamner, Robin Hurley, Pran Iruvanti, Frank Jacono, Darshana Jhala, Scott Kinlay, Jon Klein, Michael Landry, Peter Liang, Suthat Liangpunsakul, Jack Lichy, C. Scott Mahan, Ronnie Marrache, Stephen Mastorides, Elisabeth Mates, Kristin Mattocks, Paul Meyer, Jonathan Moorman, Timothy Morgan, Maureen Murdoch, James Norton, Olaoluwa Okusaga, Kris Ann Oursler, Ana Palacio, Samuel Poon, Emily Potter, Michael Rauchman, Richard Servatius, Satish Sharma, River Smith, Peruvemba Sriram, Patrick Strollo Jr., Neeraj Tandon, Gerardo Villareal, Agnes Wallbom, Jessica Walsh, John Wells, Jeffrey Whittle, Mary Whooley, Allison E. Williams, Peter Wilson, Junzhe Xu, Shing Shing Yeh
Journal: JAMA Network Open (2023)

Importance Clinical trial data have called into question the efficacy of thiazide diuretics for the prevention of kidney stones. Objective To identify whether there is an association between genetic proxies of thiazide diuretics and the risk of kidney stones. Design, Setting, and Participants This genetic association study undertook a mendelian randomization analysis of derived exposures and outcomes from genome-wide association study summary statistics. Genetic proxies of thiazide diuretics were derived from the International Consortium for Blood Pressure. Kidney stone cases and controls were derived from the Million Veteran Program, UK Biobank, and the FinnGen study. These cross-sectional designs do not report a duration of follow-up. Data analysis was performed in May 2023. Exposure Genetic proxies of thiazide diuretics were genetic variants in the thiazide-sensitive sodium chloride cotransporter gene associated with systolic blood pressure. Genetic proxies of β-blockers and systolic blood pressure served as negative controls. Main Outcomes and Measures The main outcome was the odds of kidney stones. The secondary outcomes were serum laboratory values relevant to the treatment of kidney stones. Results The main analysis included up to 1 079 657 individuals, including 50 832 kidney stone cases and 1 028 825 controls. In a meta-analysis of all cohorts, genetic proxies of thiazide diuretics were associated with a lower odds of kidney stones (OR, 0.85; 95% CI, 0.81-0.89; P &amp;amp;lt; .001). Genetic proxies of β-blockers (OR, 1.02; 95% CI, 0.96-1.07; P = .52) and systolic blood pressure (OR, 1.00; 95% CI, 1.00-1.01; P = .49) were not associated with kidney stones. Genetic proxies of thiazide diuretics were associated with higher serum calcium (β [SE], 0.051 [0.0092]; P &amp;amp;lt; .001) and total cholesterol (β [SE], 0.065 [0.015]; P &amp;amp;lt; .001), but lower serum potassium (β [SE], −0.073 [0.022]; P &amp;amp;lt; .001). Conclusions and Relevance In this genetic association study, genetic proxies of thiazide diuretics were associated with reduced kidney stone risk. This finding reflects a drug effect over the course of a lifetime, unconstrained by the limited follow-up period of clinical trials.